Loading…
The substitutions G245C and G245D in the Zn(2+)-binding pocket of the p53 protein result in differences of conformational flexibility of the DNA-binding domain
Transcription activation of the proapoptotic target genes is a means by which the p53 protein implements its function of tumor suppression. Zn(2+) is a known regulator of p53 binding to the target genes. We have previously obtained an evidence that amino acid substitutions in the p53 Zn(2+)-binding...
Saved in:
| Published in: | Journal of biomolecular structure & dynamics 2013, Vol.31 (1), p.78-86 |
|---|---|
| Main Authors: | , , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | |
|---|---|
| cites | |
| container_end_page | 86 |
| container_issue | 1 |
| container_start_page | 78 |
| container_title | Journal of biomolecular structure & dynamics |
| container_volume | 31 |
| creator | Pintus, S S Ivanisenko, N V Demenkov, P S Ivanisenko, T V Ramachandran, S Kolchanov, N A Ivanisenko, V A |
| description | Transcription activation of the proapoptotic target genes is a means by which the p53 protein implements its function of tumor suppression. Zn(2+) is a known regulator of p53 binding to the target genes. We have previously obtained an evidence that amino acid substitutions in the p53 Zn(2+)-binding pocket can presumably exert an influence on Zn(2+) position in the Zn(2+)-p53 complex and thereby affect p53 binding to DNA. With these background considerations, our aim was to estimate the effect of the putative changes in the Zn(2+) position in its binding pocket due to the G245C and G245D substitutions on the conformation of the p53 DNA-binding motif. Statistical analysis of the molecular dynamics (MD) trajectories of the mutant p53-Zn(2+) complexes was used to detect significant deviations in conformation of the mutant p53 forms. MD simulations demonstrated that (1) the two substitutions in the Zn(2+)-binding pocket caused changes in the conformation of the p53 DNA-binding motif, as compared with the wild-type (WT) p53; (2) binding of Zn(2+) to the p53 mutant forms reduced the effect of the substitutions on conformational change; and (3) Zn(2+) binding in the normal position compensated the effect of the mutations on the conformation in comparison to the altered Zn(2+) position. |
| doi_str_mv | 10.1080/07391102.2012.691364 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_1237510060</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1237510060</sourcerecordid><originalsourceid>FETCH-LOGICAL-p126t-869181fd67657ead518f2e7e2a477394bff2d281281c04276a9877836a91180c3</originalsourceid><addsrcrecordid>eNo9kNFKwzAUhoMgbk7fQCSXE-nMSdomvRybTmHozbzxpqRtotE2rU0K7ml8VTPdhAP_gfOdc_h_hC6AzIAIckM4ywAInVECdJZmwNL4CI0hYSIiNIlH6NS5d0IoAIcTNKJUEMYzGKPvzZvCbiicN37wprUOr2icLLC01W-3xMZiH6AXO6XXV1FhbGXsK-7a8kN53OrfYZcw3PWtVwHulRtqv1urjNaqV7ZUbgeWrdVt38jdG1ljXasvU5ja-O3hzPJx_v-gahtp7Bk61rJ26nyvE_R8d7tZ3Efrp9XDYr6OOqCpj0TwLEBXKU8TrmSVgNBUcUVlzEM2caE1raiAUCWJKU9lJjgXLCiAICWboOnf3eDic1DO541xpapraVU7uBwo4wkQkpKAXu7RoWhUlXe9aWS_zQ-hsh9pZ3ZZ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1237510060</pqid></control><display><type>article</type><title>The substitutions G245C and G245D in the Zn(2+)-binding pocket of the p53 protein result in differences of conformational flexibility of the DNA-binding domain</title><source>Taylor and Francis Science and Technology Collection</source><creator>Pintus, S S ; Ivanisenko, N V ; Demenkov, P S ; Ivanisenko, T V ; Ramachandran, S ; Kolchanov, N A ; Ivanisenko, V A</creator><creatorcontrib>Pintus, S S ; Ivanisenko, N V ; Demenkov, P S ; Ivanisenko, T V ; Ramachandran, S ; Kolchanov, N A ; Ivanisenko, V A</creatorcontrib><description>Transcription activation of the proapoptotic target genes is a means by which the p53 protein implements its function of tumor suppression. Zn(2+) is a known regulator of p53 binding to the target genes. We have previously obtained an evidence that amino acid substitutions in the p53 Zn(2+)-binding pocket can presumably exert an influence on Zn(2+) position in the Zn(2+)-p53 complex and thereby affect p53 binding to DNA. With these background considerations, our aim was to estimate the effect of the putative changes in the Zn(2+) position in its binding pocket due to the G245C and G245D substitutions on the conformation of the p53 DNA-binding motif. Statistical analysis of the molecular dynamics (MD) trajectories of the mutant p53-Zn(2+) complexes was used to detect significant deviations in conformation of the mutant p53 forms. MD simulations demonstrated that (1) the two substitutions in the Zn(2+)-binding pocket caused changes in the conformation of the p53 DNA-binding motif, as compared with the wild-type (WT) p53; (2) binding of Zn(2+) to the p53 mutant forms reduced the effect of the substitutions on conformational change; and (3) Zn(2+) binding in the normal position compensated the effect of the mutations on the conformation in comparison to the altered Zn(2+) position.</description><identifier>EISSN: 1538-0254</identifier><identifier>DOI: 10.1080/07391102.2012.691364</identifier><identifier>PMID: 22803791</identifier><language>eng</language><publisher>England</publisher><subject>Amino Acid Substitution ; Binding Sites ; Carrier Proteins - chemistry ; Carrier Proteins - pharmacology ; DNA - chemistry ; DNA - metabolism ; Molecular Dynamics Simulation ; Mutation ; Protein Conformation ; Tumor Suppressor Protein p53 - chemistry ; Tumor Suppressor Protein p53 - metabolism ; Zinc - chemistry ; Zinc - metabolism</subject><ispartof>Journal of biomolecular structure & dynamics, 2013, Vol.31 (1), p.78-86</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,4043,27956,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22803791$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pintus, S S</creatorcontrib><creatorcontrib>Ivanisenko, N V</creatorcontrib><creatorcontrib>Demenkov, P S</creatorcontrib><creatorcontrib>Ivanisenko, T V</creatorcontrib><creatorcontrib>Ramachandran, S</creatorcontrib><creatorcontrib>Kolchanov, N A</creatorcontrib><creatorcontrib>Ivanisenko, V A</creatorcontrib><title>The substitutions G245C and G245D in the Zn(2+)-binding pocket of the p53 protein result in differences of conformational flexibility of the DNA-binding domain</title><title>Journal of biomolecular structure & dynamics</title><addtitle>J Biomol Struct Dyn</addtitle><description>Transcription activation of the proapoptotic target genes is a means by which the p53 protein implements its function of tumor suppression. Zn(2+) is a known regulator of p53 binding to the target genes. We have previously obtained an evidence that amino acid substitutions in the p53 Zn(2+)-binding pocket can presumably exert an influence on Zn(2+) position in the Zn(2+)-p53 complex and thereby affect p53 binding to DNA. With these background considerations, our aim was to estimate the effect of the putative changes in the Zn(2+) position in its binding pocket due to the G245C and G245D substitutions on the conformation of the p53 DNA-binding motif. Statistical analysis of the molecular dynamics (MD) trajectories of the mutant p53-Zn(2+) complexes was used to detect significant deviations in conformation of the mutant p53 forms. MD simulations demonstrated that (1) the two substitutions in the Zn(2+)-binding pocket caused changes in the conformation of the p53 DNA-binding motif, as compared with the wild-type (WT) p53; (2) binding of Zn(2+) to the p53 mutant forms reduced the effect of the substitutions on conformational change; and (3) Zn(2+) binding in the normal position compensated the effect of the mutations on the conformation in comparison to the altered Zn(2+) position.</description><subject>Amino Acid Substitution</subject><subject>Binding Sites</subject><subject>Carrier Proteins - chemistry</subject><subject>Carrier Proteins - pharmacology</subject><subject>DNA - chemistry</subject><subject>DNA - metabolism</subject><subject>Molecular Dynamics Simulation</subject><subject>Mutation</subject><subject>Protein Conformation</subject><subject>Tumor Suppressor Protein p53 - chemistry</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Zinc - chemistry</subject><subject>Zinc - metabolism</subject><issn>1538-0254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNo9kNFKwzAUhoMgbk7fQCSXE-nMSdomvRybTmHozbzxpqRtotE2rU0K7ml8VTPdhAP_gfOdc_h_hC6AzIAIckM4ywAInVECdJZmwNL4CI0hYSIiNIlH6NS5d0IoAIcTNKJUEMYzGKPvzZvCbiicN37wprUOr2icLLC01W-3xMZiH6AXO6XXV1FhbGXsK-7a8kN53OrfYZcw3PWtVwHulRtqv1urjNaqV7ZUbgeWrdVt38jdG1ljXasvU5ja-O3hzPJx_v-gahtp7Bk61rJ26nyvE_R8d7tZ3Efrp9XDYr6OOqCpj0TwLEBXKU8TrmSVgNBUcUVlzEM2caE1raiAUCWJKU9lJjgXLCiAICWboOnf3eDic1DO541xpapraVU7uBwo4wkQkpKAXu7RoWhUlXe9aWS_zQ-hsh9pZ3ZZ</recordid><startdate>2013</startdate><enddate>2013</enddate><creator>Pintus, S S</creator><creator>Ivanisenko, N V</creator><creator>Demenkov, P S</creator><creator>Ivanisenko, T V</creator><creator>Ramachandran, S</creator><creator>Kolchanov, N A</creator><creator>Ivanisenko, V A</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>2013</creationdate><title>The substitutions G245C and G245D in the Zn(2+)-binding pocket of the p53 protein result in differences of conformational flexibility of the DNA-binding domain</title><author>Pintus, S S ; Ivanisenko, N V ; Demenkov, P S ; Ivanisenko, T V ; Ramachandran, S ; Kolchanov, N A ; Ivanisenko, V A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p126t-869181fd67657ead518f2e7e2a477394bff2d281281c04276a9877836a91180c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amino Acid Substitution</topic><topic>Binding Sites</topic><topic>Carrier Proteins - chemistry</topic><topic>Carrier Proteins - pharmacology</topic><topic>DNA - chemistry</topic><topic>DNA - metabolism</topic><topic>Molecular Dynamics Simulation</topic><topic>Mutation</topic><topic>Protein Conformation</topic><topic>Tumor Suppressor Protein p53 - chemistry</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Zinc - chemistry</topic><topic>Zinc - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pintus, S S</creatorcontrib><creatorcontrib>Ivanisenko, N V</creatorcontrib><creatorcontrib>Demenkov, P S</creatorcontrib><creatorcontrib>Ivanisenko, T V</creatorcontrib><creatorcontrib>Ramachandran, S</creatorcontrib><creatorcontrib>Kolchanov, N A</creatorcontrib><creatorcontrib>Ivanisenko, V A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of biomolecular structure & dynamics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pintus, S S</au><au>Ivanisenko, N V</au><au>Demenkov, P S</au><au>Ivanisenko, T V</au><au>Ramachandran, S</au><au>Kolchanov, N A</au><au>Ivanisenko, V A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The substitutions G245C and G245D in the Zn(2+)-binding pocket of the p53 protein result in differences of conformational flexibility of the DNA-binding domain</atitle><jtitle>Journal of biomolecular structure & dynamics</jtitle><addtitle>J Biomol Struct Dyn</addtitle><date>2013</date><risdate>2013</risdate><volume>31</volume><issue>1</issue><spage>78</spage><epage>86</epage><pages>78-86</pages><eissn>1538-0254</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Transcription activation of the proapoptotic target genes is a means by which the p53 protein implements its function of tumor suppression. Zn(2+) is a known regulator of p53 binding to the target genes. We have previously obtained an evidence that amino acid substitutions in the p53 Zn(2+)-binding pocket can presumably exert an influence on Zn(2+) position in the Zn(2+)-p53 complex and thereby affect p53 binding to DNA. With these background considerations, our aim was to estimate the effect of the putative changes in the Zn(2+) position in its binding pocket due to the G245C and G245D substitutions on the conformation of the p53 DNA-binding motif. Statistical analysis of the molecular dynamics (MD) trajectories of the mutant p53-Zn(2+) complexes was used to detect significant deviations in conformation of the mutant p53 forms. MD simulations demonstrated that (1) the two substitutions in the Zn(2+)-binding pocket caused changes in the conformation of the p53 DNA-binding motif, as compared with the wild-type (WT) p53; (2) binding of Zn(2+) to the p53 mutant forms reduced the effect of the substitutions on conformational change; and (3) Zn(2+) binding in the normal position compensated the effect of the mutations on the conformation in comparison to the altered Zn(2+) position.</abstract><cop>England</cop><pmid>22803791</pmid><doi>10.1080/07391102.2012.691364</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | EISSN: 1538-0254 |
| ispartof | Journal of biomolecular structure & dynamics, 2013, Vol.31 (1), p.78-86 |
| issn | 1538-0254 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1237510060 |
| source | Taylor and Francis Science and Technology Collection |
| subjects | Amino Acid Substitution Binding Sites Carrier Proteins - chemistry Carrier Proteins - pharmacology DNA - chemistry DNA - metabolism Molecular Dynamics Simulation Mutation Protein Conformation Tumor Suppressor Protein p53 - chemistry Tumor Suppressor Protein p53 - metabolism Zinc - chemistry Zinc - metabolism |
| title | The substitutions G245C and G245D in the Zn(2+)-binding pocket of the p53 protein result in differences of conformational flexibility of the DNA-binding domain |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-22T12%3A27%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20substitutions%20G245C%20and%20G245D%20in%20the%20Zn(2+)-binding%20pocket%20of%20the%20p53%20protein%20result%20in%20differences%20of%20conformational%20flexibility%20of%20the%20DNA-binding%20domain&rft.jtitle=Journal%20of%20biomolecular%20structure%20&%20dynamics&rft.au=Pintus,%20S%20S&rft.date=2013&rft.volume=31&rft.issue=1&rft.spage=78&rft.epage=86&rft.pages=78-86&rft.eissn=1538-0254&rft_id=info:doi/10.1080/07391102.2012.691364&rft_dat=%3Cproquest_pubme%3E1237510060%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-p126t-869181fd67657ead518f2e7e2a477394bff2d281281c04276a9877836a91180c3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1237510060&rft_id=info:pmid/22803791&rfr_iscdi=true |